Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX inhibitors

Abstract

The design, synthesis and biological evaluation of a library of 1,2,3-triazole carboxylates incorporating carboxylic acid, hydroxymethyl, carboxylic acid hydrazide, carboxamide and benzenesulfonamide moieties is disclosed. All the novel compounds were investigated for their inhibition potential against carbonic anhydrase (CA, EC 4.2.1.1) human (h) isoforms hCA I, II, IV and IX, well established drug targets. The cytosolic isoform hCA I was inhibited with Ki's ranging between 53.2 nM and 7.616 μM whereas the glaucoma associated cytosolic isoform hCA II was inhibited with Ki's in the range 21.8 nM-0.807 μM. The membrane bound isoform hCA IV, involved in glaucoma and retinitis pigmentosa among others, was effectively inhibited by some of these compounds with Ki < 60 nM, better than the reference drug acetazolamide (AAZ). The tumor associated isoform hCA IX, a recently validated antitumor/antimetastatic drug target, was also effectively inhibited by some of the new sulfonamides, which possess thus the potential to be used as tools for exploring in more details the selective inhibition of hCAs involved in various pathologies.